LAUSR

We read with interest the review on statins by Azemawah and colleagues, but we considered that there were certain important errors and omissions [1]. The authors provided several conflicting statements about the association of new onset diabetes mellitus (NODM) with statin treatment, and they concluded in the abstract that this is rare, controversial, and not proven. We consider this is well proven from the large clinical trials with statins, observational studies, and the Mendelian randomization study [2]. Notably, the Mendelian randomization study also predicted that the loss of function variants in the gene for proprotein convertase subtilisin-kexin type 9 (PCSK9) were also associated with NODM [3], but this has not been seen in the clinical trials with the monoclonal antibodies inhibiting PCSK9. These antibodies only inhibit circulating PCSK9, and it will be interesting to see if inclisiran, which inhibits intracellular PCSK9 production, is associated with NODM in the long-term studies. The risk of NODM with statins increases in subjects with the metabolic syndrome or prediabetes and with increasing intensity of statin therapy reaching 34% increased risk with atorvastatin 80 mg [4]. The authors stated that pravastatin has never been shown to have any diabetic effects, but actually there was a significant 32% increase in NODM with pravastatin 40 mg compared to placebo in the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial [5]. Overall, the least risk of NODM is seen with pitavastatin [4], which was not mentioned in the review, although it was approved by the FDA in 2009. Pitavastatin is also the statin with the least propensity for drug–drug interactions and the greatest in vitro binding affinity to HMG-CoA reductase of all the currently available statins. The small excess of NODM with statins was detected by large-scale randomized trials, as was a small excess of hemorrhagic stroke (not mentioned in the review), but these trials failed to detect a long-term increase in muscle-related symptoms with statins [6]. The role of statins in the milder forms of muscle symptoms is disputed and has been attributed to a nocebo effect, but there is no dispute that statins can cause severe myopathy and potentially fatal rhabdomyolysis, which appears to be related to the statin concentration in skeletal muscle reaching a critical threshold. Azemawah and colleagues discuss the role of drug metabolizing enzymes in drug interactions with statins but do not mention the important role of drug transporters in statin disposition and toxicity. The genome-wide association study to identify genetic associations of definite or incipient myopathy with 80 mg simvastatin daily (2.3% over a mean follow-up of 6∙7 years) from the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial identified the noncoding rs4363657 single-nucleotide polymorphism (SNP) in the SLCO1B1 gene encoding the organic anion-transporting polypeptide 1B1 (OATP1B1) liver uptake transporter, which was in nearly complete linkage disequilibriumwith the functional rs4149056 (c.521T>C, p. Val174Ala) SNP, known to influence the liver uptake of simvastatin acid [7]. Over 60% of the myopathy cases in that study could be attributed to the SLCO1B1 C variant. The influence of the SLCO1B1 rs4149056 SNP on the risk of myopathy with high-dose simvastatin was also the subject Brian Tomlinson and Paul Chan contributed equally to this work.